Identification of novel intercellular signaling molecules of the animal central nervous system

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In addition to neurons, the brain contains several types of non-neuronal support cells called glia that secrete growth factors and other molecules needed for neuronal survival. However, glia can also be induced to secrete neurotoxic substances. Whether glia promote neuronal survival or damage depends on the stimuli present in their surrounding environment. The exact network of intercellular signaling molecules involved in glia-neuronal and glia-glial communication remains to be elucidated. Specifically, the following questions are unanswered: 1) What molecules released by stimulated and/or damaged glia and neurons are recognized by surrounding glia; 2) If glia respond differently to distinct endogenous molecules, what are the key features of such responses? The OVERALL OBJECTIVE of the proposed research program is to identify novel proteins that function as intercellular signals in the animal brain and explore their cellular and molecular mechanisms of action. Through collaborative work, I have already identified two candidate proteins, mitochondrial transcription factor (TFAM) and cytochrome c, which are normally hidden inside cell organelles called mitochondria, but could interact with glia once released from cells. Two of the specific objectives of the proposed research program will generate data that either support or dismiss these two and other candidate proteins as signaling molecules used by brain cells. My students and I will identify the receptors and intracellular signaling pathways involved in glia-TFAM interactions. TFAM protein will also be injected into rat brains and cellular responses will be measured. Under the third objective, large-scale protein analysis (proteomics) will be used to identify changes in glial secretions induced by TFAM and its associated molecules. Overall, this research will identify proteins that belong to the network of intercellular signaling molecules of the brain. The data generated will benefit the field of neurobiology by providing fundamental knowledge about these networks. Moreover, this research program could lead to practical applications benefitting all Canadians through identification of molecular targets for altering or improving brain function.